Pyran derivatives

ABSTRACT

Compounds of formula I: ##STR1## wherein: R1 is hydrogen or alkyl; 
     R2 is alkyl optionally substituted by one or more alkoxy groups or halogen atoms; 
     X is a group of formula --OR3 wherein R3 is alkyl, cycloalkyl, or arylalkyl; or X is a group of formula --NHCVR4 wherein V is oxygen or sulphur, R4 is hydrogen, alkyl, cycloalkyl (which alkyl and cycloalkyl groups may be substituted), alkenyl, aryl, arylalkyl, amino, mono- or di-alkylamino or a group of the formula --OR5 wherein R5 is optionally substituted alkyl, aryl or arylalkyl; or X is a group of formula --NHSO 2  R4a wherein R4a is alkyl, aryl or a group of formula --CH 2  COR4b wherein R4b is alkyl or aryl; 
     Y is optionally substituted alkoxy, cycloalkoxy, arylalkoxy or a group of formula --NR6R7 wherein R6 is hydrogen or alkyl and R7 is alkyl, cycloalkyl (which alkyl and cycloalkyl groups may be substituted), aryl or arylalkyl or R7 is a group of formula --COOR8 wherein R8 is alkyl are useful intermediates in the synthesis of beta-lactam antibiotics.

This is a division of application Ser. No. 07/334,749, filed Apr. 6,1989, now U.S. Pat. No. 5,155,236 which is a continuation of applicationSer. No. 06/942,437, filed Dec. 16, 1986, now abandoned.

The invention relates to compounds useful as intermediates in thesynthesis of beta-lactam antibiotics, particularly carbapenems, and to aprocess for the manufacture of the said compounds.

In this specification chemical formulae (denoted by Roman numerals) areset out graphically on separate sheets. Numbered groups, e.g. R1, R2etc. used in more than one formula are to be taken as having the samemeaning throughout the specification unless otherwise stated.

Unless otherwise indicated herein alkyl means (1-6C)alkyl, cycloalkylmeans (3-7C)cycloalkyl or bridged (6-9C)bicycloalkyl, aryl means anoptionally substituted 5- or 6-membered carbocyclic or heterocyclic arylgroup (containing, when heterocyclic, 1, 2 or 3 heteroatoms selectedfrom O, N and S), arylalkyl means aryl(1-4C)alkyl, alkoxy means(1-6C)alkoxy, cycloalkoxy means (3-7C)cycloalkoxy or bridged(6-9C)bicycloalkoxy and alkenyl means (2-6C)alkenyl.

In a first aspect the invention provides compounds of formula I wherein:

R1 is hydrogen or alkyl;

R2 is alkyl optionally substituted by one or more alkoxy groups orhalogen atoms;

X is a group of formula --OR3 wherein R3 is alkyl, cycloalkyl, orarylalkyl; or X is a group of formula --NHCVR4 wherein V is oxygen orsulphur, R4 is hydrogen, alkyl, cycloalkyl (which alkyl and cycloalkylgroups may be substituted), alkenyl, aryl, arylalkyl, amino, mono- ordi-alkylamino or a group of the formula --OR5 wherein R5 is optionallysubstituted alkyl, aryl or arylalkyl; or X is a group of formula --NHSO₂R4a wherein R4a is alkyl, aryl or a group of formula --CH₂ COR4b whereinR4b is alkyl or aryl;

Y is optionally substituted alkoxy, cycloalkoxy, arylalkoxy or a groupof formula --NR6R7 wherein R6 is hydrogen or alkyl and R7 is alkyl,cycloalkyl (which alkyl and cycloalkyl groups may be substituted), aryl,arylalkyl or R7 is a group of formula --COOR8 wherein R8 is alkyl orarylalkyl;

In a particular aspect the invention provides compounds of formula Iwherein:

R1 is hydrogen or (1-4C)alkyl;

R2 is alkyl optionally substituted by one or more (1-4C)alkoxy groups orhalogen atoms;

X is a group of formula --OR3 wherein R3 is alkyl, cycloalkyl, orarylalkyl; or X is a group of formula --NHCVR4 wherein V is oxygen, R4is hydrogen, alkyl, cycloalkyl (which alkyl and cycloalkyl groups may besubstituted), alkenyl, aryl, arylalkyl, amino, mono- ordi-(1-4C)alkylamino or a group of the formula --OR5 wherein R5 isoptionally substituted alkyl, aryl or arylalkyl; or X is a group offormula --NHSO₂ R4a wherein R4a is alkyl, aryl or a group of formula--CH₂ COR4b wherein R4b is alkyl or aryl;

Y is optionally substituted alkoxy, cycloalkoxy, arylalkoxy or a groupof formula --NR6R7 wherein R6 is hydrogen or (1-4C)alkyl and R7 is(1-4C)alkyl, cycloalkyl (which alkyl and cycloalkyl groups may besubstituted), aryl, arylalkyl, or R7 is a group of formula --COOR8wherein R8 is (1-4C)alkyl or arylalkyl;

Where any of the above alkyl or cycloalkyl groups are substituted, thesubstituent(s) may be for example one or more halogen (e.g. fluorine orchlorine) atoms or alkoxy groups unless otherwise specified.

Optional substitutent(s) on an alkyl group R5 may be for example one ormore halogen (e.g. fluorine or chlorine) atoms.

An optional substituent on an alkoxy or cycloalkoxy group Y may be forexample a carboxy or (1-4C)alkoxycarbonyl group.

Optional substituent(s) on an aryl group herein may be for examplehalogen, alkyl, (1-4C)alkoxy or (2-6C)alkoxycarbonyl.

Particular meanings for R1 are hydrogen or a methyl group.

A particular meaning for R2 is methyl, optionally substituted by one ormore fluorine atoms.

Particular meanings for the group X are methoxy, ethoxy or benzyloxy ora group of the formula --NHCOR₄ wherein R4 is hydrogen or methyl, ethyl,ethenyl, phenyl, benzyl, methoxy, ethoxy, amino, trifluoroethoxy,trichloroethoxy, phenoxy or benzyloxy.

Particular meanings for the group Y are methoxy, ethoxy or benzyloxy ora group of the formula NR6R7 wherein R6 is hydrogen and R7 is methyl,ethyl, phenyl, benzyl, α-methylbenzyl, methoxycarbonyl orethoxycarbonyl.

A particular meaning for an aryl group is phenyl and particular meaningsfor the optional substituent(s) on the phenyl group are fluorine,chlorine, bromine, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl orethoxycarbonyl.

The compounds of formula I may be prepared from compounds of formula IIwherein R9 is (1-12C)alkyl, cycloalkyl (which alkyl and cycloalkylgroups may be substituted) or arylalkyl, by reduction e.g. with sodiumborohydride or a hydrosilane or trialkylsilane (e.g. triethylsilane) inacid solution (e.g. in trifluoroacetic acid), conveniently at roomtemperature.

The compounds of formula II are novel and form a further feature of theinvention.

Optional substituents on an alkyl or cycloalkyl group R9 may be forexample one or more halogen (e.g. fluorine or chlorine) atoms, hydroxyor alkoxy groups.

Particular meanings for R9 are methyl, ethyl, benzyl.

The compounds of formula II may in turn be prepared by one of thefollowing methods:

Method (1)

Hydrolysis of a compound of formula III wherein R10 and R11 (which maybe the same or different) are selected from (1-12C)alkyl, cycloalkyl(which alkyl and cycloalkyl groups may be substituted) arylalkyl orsilyl (bearing alkyl, aryl or arylalkyl substituents) or R10 and R11 arejoined to form a 5- or 6-membered cyclic acetal which may besubstituted, e.g. by alkyl, carboxy or (1-7C)alkoxycarbonyl. Thehydrolysis is conveniently carried out under acid conditions e.g. withdilute mineral acid e.g. HCl preferably in an organic solvent e.g.methanol, ethanol, tetrahydrofuran, conveniently at room temperature.

Particular meanings for R10 and R11 are methyl, ethyl, benzyl,trimethylsilyl and dimethyl-t-butylsilyl.

The compounds of formula III may themselves be prepared by reaction of acompound of formula IV with a compound of formula V.

The compounds of formula (IV), and the compounds of formula (V) whereinR10 and R11 are not the same, can each exist in two isomeric forms andthe process of the invention extends to the use of either of each pairof isomers separately or of mixtures of isomers.

The reaction between the compounds of formulae IV and V is convenientlycarried out in an organic solvent e.g. toluene, xylene, acetonitrile, ahalogenated hydrocarbon (e.g. methylene chloride, chloroform), or anether (e.g. diethyl ether, tetrahydrofuran, dioxan) optionally in thepresence of a catalyst, e.g. a Lewis acid catalyst, for example a rareearth complex. The use of the catalyst may influence the overall yieldof the product and also the relative amounts of the isomers of productsof formula (III) about the C3 and C4 positions which are produced. Thereaction is conveniently carried out at temperatures up to about 120° C.for example from 0°-100° C.

Method (2)

Reaction of a compound of formula IV with a compound of formula Vdirectly, in particular where one or both of R10 and R11 represents asilyl group and the reaction is carried out as described above but inthe presence of a titanium tetrachloride or fluoride ion catalyst.

The compounds of formula I are, as stated, useful intermediates in thepreparation of beta-lactam antibiotics. Thus they may be converted, bysimultaneous or sequential hydrolysis of the groups X and Y (e.g. byheating with strong acid, e.g. HCl) to compounds of the formula VI. Thecompounds of formula VI wherein R1 is other than hydrogen are themselvesnovel and form further features of the invention.

Compounds of formula VI may be converted, by methods known in theliterature for analogous compounds or by methods analogous to suchmethods, (for example D G Melillo, I Shinkai, T Liu, K Ryan and MSletzinger, Tetrahedron Letters, vol. 21, p. 2783 (1980)) toazetidinones of the formula VII, where R12 is for example an alkyl oraralkyl group, e.g. a methyl or benzyl group.

Compounds of formula VII are known to be useful intermediates for theproduction of antibiotics, in particular carbapenem antibiotics.

It will be understood that compounds of formula VII contain up to fourasymmetric centres. It is desirable that the said compounds should havethe stereochemistry illustrated in formula VIIa and the process of theinvention is advantageously operated in such a way that compounds havingthe formula VIIa may be produced eg by chiral synthesis, if necessaryafter subsequent treatment and/or separation of isomers or by resolutionof optical isomers at a suitable stage. Achievement of the correctstereochemistry in the compound of formula VIIa may be facilitated bythe use of compounds in which one or more of the groups R9, R10, X and Yare chiral.

The invention is illustrated, but not limited, by the followingExamples, in which n.m.r. means nuclear magnetic resonance spectroscopy,m.p. means melting point and b.p., means boiling point. The n.m.r.spectra were taken at 200 MHz in the solvent indicated and are quoted indelta values in parts per million (ppm). In the quotation of the n.m.r.spectra standard abbreviations are used e.g. s=singlet, d=doublet,q=quartet, m=multiplet, br=broad.

EXAMPLES 1-25

Compounds of formula III may be prepared as follows:

EXAMPLE 1

N-Ethoxycarbonyl-2-ethoxymethylene-3-oxobutanamide (2.3 g) was dissolvedin toluene (15 ml) and treated dropwise with 1,1-di-ethoxyprop-1-ene (2g). The mixture was stirred at 40° C. for 2 hours and evaporated todryness. The residual oil was purified by medium pressure liquidchromatography on K60 silica using ethyl acetate/petroleum ether b.p.60°-80° C. 15/85 v/v and 20/80 v/v as eluting solvents, to give aftertrituration with n-hexanetrans-2,2-diethoxy-3,6-dimethyl-4-ethoxy-N-ethoxycarbonyl-3,4-dihydro-2H-pyran-5-carboxamide(0.6 g) m.p. 84°-7° C. The n.m.r spectrum in deuterochloroform displayedthe --CH(OEt)-- signal at 3.9 ppm (doublet of quartets, 1H J=3 Hz and 1Hz), which is indicative of the trans arrangement of the 3 and 4substituents.

EXAMPLE 2

N-ethoxycarbonyl-2-ethoxymethylene-3-oxobutanamide (1.2 g) andtris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)ytterbium(0.27 g) were stirred in toluene (10 ml) and 1,1-diethoxyprop-1-ene (1g) was added dropwise. The mixture was stirred at room temperature forthree hours and evaporated to dryness. The residual oil was partitionedbetween diethyl ether and water and the organic layer was separated,dried over anhydrous magnesium sulphate, and evaporated to dryness. Theresidual oil was purified by medium pressure liquid chromatography onK60 silica using ethyl acetate/petroleum ether, b.p. 60°-80° C., 15/85v/v and 20/80 v/v as eluting solvents to give, after trituration withn-hexane,trans-2,2-diethoxy-3,6-dimethyl-4-ethoxy-N-ethoxycarbonyl-3,4-dihydro-2H-pyran-5-carboxamide(0.5 g), m.p. 86°-8° C.

EXAMPLE 3

N-(4'-Chlorophenyl)-2-ethoxymethylene-3-oxobutanamide (1.3 g) wasstirred in toluene (10 ml) whilst 1,1-diethoxyprop-1-ene (2 g) was addeddropwise. The mixture was stirred at room temperature for 40 hours andevaporated to dryness. The residual gum was purified by medium pressureliquid chromatography on K60 silica using ethyl acetate/petroleum etherb.p. 60°-80° C. 15/85 v/v as eluting solvent to give two stereoisomers.The first isomer after trituration with n-hexane gavetrans-N-(4'-chlorophenyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide(0.6 g), m.p. 104°-106° C. The n.m.r. spectrum (deuterochloroform)showed the --CH(OEt)-- signal at 4.0 ppm (doublet of quartets 1H, J=3 Hzand 1 Hz), consistent with the trans-configuration. The second isomer,after trituration with n-hexane, gavecis-N-(4'-chlorophenyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide(0.1 g), m.p. 125°-7° C. The n.m.r. spectrum (deuterochloroform) showedthe --CH(OEt)-- signal at 4.5 ppm (doublet of quartets, 1H, J=7 Hz and 1Hz) consistent with the cis-configuration.

EXAMPLE 4

N-(4'-Chlorophenyl)-2-ethoxymethylene-3-oxobutanamide (1.3 g) and tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedianato)ytterbium(0.26 g) were stirred in toluene (10 ml) whilst 1,1-diethoxyprop-1-ene(2 g) was added dropwise. The mixture was stirred at room temperaturefor two hours and evaporated to dryness. The residual gum was purifiedby medium pressure liquid chromatography on K60 silica using ethylacetate/petroleum ether b.p. 60°-80° C., 15/85 v/v as eluting solvent togive two stereoisomers. The first isomer after trituration with n-hexanegavetrans-N-(4'-chlorophenyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide(0.2 g), m.p. 104°-106° C. The second isomer, again after triturationwith n-hexane, gavecis-N-(4'-chlorophenyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide(1.3 g), m.p. 125°-127° C.

EXAMPLE 5

N-(4'-chlorobenzyl)-2-ethoxymethylene-3-oxobutanamide (1.4 g) and tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedianato)ytterbium(0.26 g) were stirred in toluene (10 ml) whilst 1,1-diethoxyprop-1-ene(4 g) was added dropwise. The mixture was stirred at room temperaturefor 3 days and evaporated to dryness. The residual gum was trituratedwith petroleum ether b.p. 60°-80° C. to give a solid which wasrecrystallised from a mixture of toluene and petroleum ether b.p.60°-80° C. to givecis-N-(4'-chlorobenzyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide(0.9 g) m.p. 97°-100° C.

The n.m.r. spectrum in deuterochloroform displayed the --CH(OEt)--signal at 4.5 ppm (doublet of quartets, 1H, J=7 Hz).

EXAMPLE 6

1,1-Diethoxyprop-1-ene (5.0 ml) was added in one portion to a stirredsolution of methyl-2-acetylaminomethylene-3-oxobutanoate (5.2 g) intoluene (15 ml) at 20°-25° C. An exothermic reaction ensued and acrystalline solid precipitated out. The reaction mixture was stirred for2 further hours at ambient temperature and the solid was then filteredoff to give methyltrans-4-acetylamino-2,2-diethoxy-3,6-dimethyl-3,4-dihydro-2H-pyran-5-carboxylate(4.0 g), m.p. 152°-154° C. The structure of this ester was ascertainedusing X-ray analysis. The n.m.r. spectrum in deuterochloroform showed asignal for the --CH(N)-- proton at 4.85 ppm (doublet of doublets ofquartets, J₃,4 =1.5, J₄,NH =9.8, J₄,7 =0.9 Hz, C₆ Me=C₇).

The filtrate was evaporated to dryness and the residual gum dissolved inboiling hexane. After charcoal treatment the residual solution oncooling gave crystalline methylcis-4-acetylamino-2,2-diethoxy-3,6-dimethyl-3,4-dihydro-2H-pyran-5-carboxylate(3.0 g), m.p. 87°-88° C. The n.m.r. spectrum in deuterochloroformdisplayed the --CH(N)-- proton at 5.12 ppm. (doublet of doublets ofquartets J₃,4 =5.4, J₄,NH 10.2, J₄,7 =0.9 Hz).

EXAMPLES 7-16

The procedure of Example 6 was used to prepare the compounds of Examples7-16, details of which are given in Table I, except that chromatographyon K60 silica, eluting with diethyl ether-hexane mixture, was used toseparate cis and trans isomers before crystallisation.

                  TABLE I                                                         ______________________________________                                         ##STR2##                                                                     Ex-                                                                           am-                                                                           ple                     trans:cis                                                                              Mpt °C.                               No.  Y         X            ratio  trans cis                                  ______________________________________                                         7   OCH.sub.3 NHCOPh       1.1:1  105-7 124-5                                 8   OCH.sub.3 NHCHO        1.5:1  113-5 (N/I)                                 9   OCH.sub.3 NHCOOCH.sub.2 Ph                                                                           1:1    N/I   72-4                                 10   OCH.sub.3 NHCOCH.sub.2 Cl                                                                            1.3:1  122-4 (N/I)                                11   OCH.sub.3 NHCOC(CH.sub.3).sub.3                                                                      1:2    (N/I) 81-2                                 12   OCH.sub.3 NHCOOCH.sub.2 CCl.sub.3                                                                    1:1    (N/I) 97-9                                 13   OCH.sub.2 CH.sub.3                                                                      NHCONH.sub.2 3.5:1  148-9 (N/I)                                14   OCH.sub.3 NHCOCHCH.sub.2                                                                             1.8:1  134-6 (N/I)                                15   OCH.sub.3 NHCOCCl.sub.3                                                                              1.3:1  oil.sup.1                                                                           oil.sup.1                            16   OCH.sub.2 Ph                                                                            NHCOOCH.sub.2 Ph                                                                           1:1    70-2  oil.sup.2                            ______________________________________                                         (Ph = Phenyl) (N/I = not isolated)                                            Footnotes                                                                      .sup.1 n.m.r. (CDCl.sub.3) trans: 1.00(d, 3H), 1.20(t, 3H), 1.30(t,          3H)2.36(d, 3H), 2.37(dq, 1H), 3.59(q, 2H), 3.70(m, 2H), 3.72(s, 3H),          4.80(ddq, 1H). The cisisomer was characterised by n.m.r. signals at           1.10(d, 3H) and 5.03(ddq).                                                    .sup.2 n.m.r. (CDCl.sub.3): 1.07(d, 3H), 1.15(t, 3H), 1.23(t, 3H), 2.25(s     3H), 2.27(dq, 1H), 3.60(m, 2H), 3.80(m, 2H), 4.90(ddq, 1H), 5.04(s, 2H),      5.13(s, 3H), 5.28(d, 1H), 7.30(m, 10H).                                  

EXAMPLE 17

1,1-Diethoxyprop-1-ene (1.0 ml) was added to a solution of methyl2-acetylaminomethylene-3-oxobutanoate (1.0 g) and tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octandionato)ytterbium (0.05g) in toluene (3.0 ml) at 20° C. After stirring for 2 hr at ambienttemperature, the reaction mixture was filtered to give methyltrans-4-acetylamino-2,2-diethoxy-3,6-dimethyl-3,4-dihydro-2H-pyran-5-carboxylate(1.05 g), m.p. 153°-4° C.

EXAMPLE 18

N-(4'-chlorophenyl)-2-(acetylaminomethylene)-3-oxobutanamide (83 g) intoluene (200 ml) was treated with 1,1-diethoxyprop-1-ene (60 ml) andheated at 100° C. for 6 hours. The mixture was evaporated and theresidue was triturated with toluene to givetrans-2,2-diethoxy-3,6-dimethyl-4-(acetylamino)-5-(4'-chlorophenylcarbamoyl)-3,4-dihydro-2H-pyran(80.5 g) m.p. 199°-201° C.

The general process of Example 18 was repeated using the appropriatediene compound to yield the compounds of Examples 19-22, of whichdetails are given in Table II, all the compounds being trans about the3,4 bond.

                  TABLE II                                                        ______________________________________                                         ##STR3##                                                                     Example                 Melting point                                         No.    Y                (°C.)                                          ______________________________________                                        19     C.sub.2 H.sub.5 OCONH                                                                           75-80                                                20     PhCH(CH.sub.3)CONH(S)                                                                          210-2      (3R, 4R).sup.1                             21     PhCH(CH.sub.3)CONH(S)                                                                          157-8      (3S, 4S).sup.1                             22     PhCH(CH.sub.3)CONH(R)                                                                          158-60     (3R, 4R)                                   ______________________________________                                         Footnote                                                                      .sup.1 The products were purified by chromatography on K60 silica using       diethyl ether as eluting solvent and subsequent recrystallisation from a      mixture of diethyl ether and hexane. The structure of the two                 diastereoisomers were determined by Xray analysis.                       

EXAMPLE 23

To a stirred solution of methyl 2-acetylamino methylene-3-oxobutanoate(18.5 g) in toluene (100 ml) at 20°-25° C. was added 1,1-dimethoxyethene (15 ml) in one portion. An exothermic reaction ensued and acrystalline solid formed, which was filtered off after stirring for 2hours at ambient temperature to give methyl4-acetylamino-2,2-dimethoxy-6-methyl-3,4-dihydro-2H-pyran-5-carboxylate(26.2 g) m.p. 160°-2° C., n.m.r. (CDCl₃) 1.95 (s, 3H), 1.98 (dd,1H),2.27 (dd,1H), 2.27 (dd,1H), 2.30 (d,3H), 3.32 (s,3H), 3.40 (s, 3H), 3.72(s,3H), 5.21 (ddq, 1H), 5.95 (d,1H).

Preparation of Starting Materials for EXAMPLES 1-23

Compounds of formula IV used as starting materials in the preparation ofcompounds of formula III may be prepared for example by the followingmethods. Where no specific method of preparation for such a startingmaterial is given, the compound is known in the literature and/or may beprepared by methods analogous to those given.

The ketene acetals of formula V (e.g. 1,1-diethoxyprop-1-ene) may beprepared for example by the method of J Amer Chem Soc. 62, 1482 (1940)or German Patent Application DE 2331675.

Preparation 1

N-(4'-chlorobenzyl)-2-ethoxymethylene-3-oxobutanamide (starting materialfor Example 5)

N-4'-chlorobenzyl-3-oxobutanamide (13 g), triethoxymethane (16 ml) andacetic anhydrdie (25 ml) were refluxed for 1.5 hours. The reactionmixture was evaporated, the residual gum was triturated with ether andthe resulting solid was recrystallised from a mixture of ethyl acetateand petroleum ether b.p. 60°-80° C. to give the title compound (7.5 g)m.p. 103°-5° C.

Preparation 2

Methyl 2-acetylaminomethylene-3-oxobutanoate (starting material forExamples 6 and 23)

Acetamide (10.0 g) and methyl 2-methoxymethylene-3-oxobutanoate (30.0ml) were heated with stirring at 100° C. for 4 hours. On cooling theproduct was flash chromatographed on Merck silica 9385 using a 50/50mixture of ether/hexane to give the title compound (18.5 g) m.p. 60°-62°C. (hexane/ether).

Preparation 3

Methyl 2-trichloroacetamidomethylene-3-oxobutanoate (starting materialfor Example 15)

Methyl 2-aminomethylene-3-oxobutanoate (1.4 g) in methylene chloride (20ml) was treated with triethylamine (2.0 ml) and trichloroacetyl chloride(2.0 ml) while stirring at 20°-25° C. The mixture was stirred for 4hours at 20° C. to give a solution of the title compound, which was usedimmediately to prepare the dihydropyran of Example 15 without isolation.

Preparation 4

N-(4'-chlorophenyl)-2-(N-acetylaminomethylene-3-oxobutanamide (startingmaterial for Example 18)

N-(4'-chlorophenyl)-2-ethoxymethylene-3-oxobutanamide (108 g), acetamide(31 g) and toluene (20 ml) were heated at 140° C. for 5 hours. Themixture was evaporated and the residue was triturated with diethyl etherto give the title compound (83.2 g) m.p. 132°-6° C.

Preparation 5

Benzyl 2-benzylcarbonylaminomethylene-3-oxobutanoate (starting materialfor Example 16)

A mixture of benzyl acetoacetate (20 ml), tribenzyl orthoformate (38ml), benzyl carbamate (15 g) and acetic anhydride (40 ml) was stirred atreflux temperature (130°-140° C.) for 16 hours. The solvents wereevaporated at reduced pressure and the residue purified bychromatography on K60 silica eluting with Et₂ 0/hexane (1:5) to give thetitle compound as an oil. n.m.r. (CDCl₃): 2.50 (s,3H), 5.20 (s,4H), 7.37(m,10H), 8.47 (d, 1H).

Preparation 6

(a) N-[(S)-1'-phenylethyl]-2-acetylaminomethylene-3-oxobutanamide(starting material for Examples 20 and 21) was prepared by the method ofPreparation 4 and purified by chromatography on K60 silica using tolueneas eluant, n.m.r. (CDCl₃): 1.5 (d,3H), 2.2 (s,3H), 2.4 (s,3H), 5.1(m,1H), 7.3 (m,5H), 8.5 (d,1H).

(b) N-[(R)-1'-phenylethyl]-2-acetylaminomethylene-3-oxobutanamide(starting material for Example 22) was prepared by the method ofPreparation 4 and purified by chromatography on K60 silica using diethylether-hexane (70-30, v/v) as eluant and recrystallisation from hexane.

Preparations 7-14

(Starting materials for the corresponding Examples 7-14) The compoundsindicated in Table III were prepared by the methods specified.

                  TABLE III                                                       ______________________________________                                         ##STR4##                                                                     Prep-                              Prepared ac-                               ara-                               cording to pro-                            tion                         M.pt. cess of Prepara-                           No.   Y         X            (°C.)                                                                        tion No:                                   ______________________________________                                         7    OCH.sub.3 NHCOPh        89-90                                                                              5                                           8    OCH.sub.3 NHCHO         90-91                                                                              2                                           9    OCH.sub.3 NHCO.sub.2 CH.sub.2 Ph                                                                      95-7 2                                          10    OCH.sub.3 NHCOCH.sub.2 Cl                                                                             78-80                                                                              2                                          11    OCH.sub.3 NHCOC(CH.sub.3).sub.3                                                                      oil.sup.1                                                                           2                                          12    OCH.sub.3 NHCO.sub.2 CH.sub.2 CCl.sub.3                                                              Note.sup.2                                                                          3                                          13    OCH.sub.2 CH.sub.3                                                                      NHCONH.sub.2 194-6 5                                          14    OCH.sub.3 NHCOCHCH.sub.2                                                                              74-6 2                                          ______________________________________                                         Footnotes                                                                     .sup.1 The product was purified by chromatography on K60 silica using         ether/hexane (1:4) as eluant, n.m.r. (CDCl.sub.3): 1.3(s, 9H), 2.5(s, 3H)     3.8(s, 3H), 8.6(d, 1H), 12.4(broad, 1H)                                       .sup.2 The solution in methylene chloride was used immediately to prepare     the dihydropyran.                                                        

Preparation 15

N-Ethoxycarbonyl-2-acetylaminomethylene-3-oxobutanamide (startingmaterial for Example 19) was prepared according to the method ofPreparation 4, m.p. 110°-3° C.

EXAMPLES 24-26

The following Examples illustrate the preparation of compounds offormula II. Analogous methods may be employed using the remainingcompounds of formulae III prepared in Examples 1-23 as startingmaterials, to obtain further compounds of formula II.

EXAMPLE 24

To a solution of methyltrans-4-acetylamino-2,2-diethoxy-3,6-dimethyl-3,4-dihydro-2H-pyran-5-carboxylate(12.2 g) (Example 6) in 200 ml tetrahydrofuran was added 3.0 ml waterand 1.0 ml 1N HCl. The mixture was stirred at 20°-25° C. for 16 hours,then neutralized by adding 1.0 g anhydrous potassium carbonate. Themixture was filtered and the filtrate evaporated at reduced pressure togive 11.4 g of crude product which was crystallised from toluene/hexane(50:50) giving ethyl2-methyl-3-acetylamino-4-methoxycarbonyl-5-oxohexanoate (6.8 g), m.p.93°-6° C.

EXAMPLE 25

Trans-2,2-diethoxy-3,6-dimethyl-4-acetylamino-5-(4'-chlorophenylcarbamoyl)-3,4-dihydro-2H-pyran(76.5 g) (Example 18) was stirred at room temperature in a mixture oftetrahydrofuran (200 ml) and 1N hydrochloric acid (10 ml) for 16 hours.The reaction mixture was diluted with water, extracted with ethylacetate and the organic extract dried in anhydrous magnesium sulphateand evaporated to dryness. The residual solid was triturated withdiethyl ether to give ethyl2-methyl-3-acetylamino-4-(4'-chlorophenylcarbamoyl)-5-oxohexanoate, 66g, m.p. 169°-73° C.

EXAMPLE 26

The above method was used to prepareethyl-2-methyl-3-acetylamino-4-[(S)-1'-phenylethylcarbamoyl]-5-oxohexanoate,m.p. 189°-90° C. from the compound of Example 21.

EXAMPLES 27-31

The following Examples illustrate the preparation of the compounds offormula I, either from compounds of formula II as isolated in Examples24-26, or from compounds of formula III as prepared in Examples 1-23without isolation of the intermediate compound of formula II. Analogousmethods can be used to prepare further compounds of formula I from theremaining compounds of formula III described in Examples 1-23.

EXAMPLE 27

To a solution of ethyl2-methyl-3-acetylamino-4-methoxycarbonyl-5-oxohexanoate (2.9 g) (Example24) in trifluoracetic acid (25 ml) at 20°-25° C. was addedtriethylsilane (4 ml). The mixture was stirred for 48 hrs., then thesolvent was evaporated at reduced pressure.

By chromatography on K60 silica with ethyl acetate as eluant, threeisomers of2-oxo-3,6-dimethyl-4-acetylamino-5-methoxycarbonyl-3,4,5,6-tetrahydro-2H-pyranwere separated:

The 3,4-trans, 4,5-trans, 5,6-trans (ttt) isomer, 1 g., m.p. 155°-6° C.n.m.r. (CDCl₃): 1.38 (d,3H), 1.39 (d,3H), 1.98 (s,3H), 2.64 (dq,1H),2.79 (dd,1H), 3.73 (s,3H), 4.26 (ddd,1H), 4.58 (d,1H), 6.0 (d,1H) the3,4-trans, 4,5-trans, 5,6-cis(ttc)isomer, 0.3 g., m.p. 109°-110° C.,n.m.r. (CDCl₃): 1.30 (d,3H), 1.39 (d,3H), 2.01 (s,3H), 3.07 (dd,1H),3.08 (dq,1H), 3.76 (s,3H), 3.80 (ddd,1H), 4.98 (dq,1H), 6.1(d,1H) the3,4-trans, 4,5-cis, 5,6-cis (tcc) isomer, 0.2 g, m.p. 215°-6° C., n.m.r.(CDCl₃): 1.36 (d,3H), 1.41 (d, 3H), 2.00 (s,3H), 2.97 (dq,1H), 3.22(dd,1H), 3.75 (s,3H), 4.19 (ddd,1H), 4.62 (dq,1H), 6.4 (d,1H).

The structures of the ttt and ttc isomers were confirmed by X-Rayanalysis.

EXAMPLE 28

To a stirred solution of the product of Example 16 (trans isomer)(1.0 g)in tetrahydrofuran (15 ml) was added 1.0 ml distilled water and 0.2 ml1N HCl. The solution was stirred at 20°-25° C. for 16 hours. Thesolvents were evaporated at reduced pressure to give an oil (1.0 g),which was dissolved in trifluoroacetic acid (4.0 ml) at 20°-25° C., thentriethylsilane (2.0 ml) was added and the mixture stirred for 16 hoursat ambient temperature. The solvents were evaporated to give a gum (1.0g) which was a mixture of isomers-chromatography on Merck silica elutingwith Et₂ O/hexane gave2-oxo-3,6-dimethyl-4-benzyloxycarbonylamino-5-benzyloxycarbonyl-3,4,5,6-tetrahydro-2H-pyran(ttt isomer) (200 g) m.p. 110°-2° C. n.m.r.(CDCl₃) 1.31 (d,3H), 1.36(d,3H), 2.65 (dq,1H), 2.85 (dd,1H), 3.95 (ddd,1H), 4.51 (dq,1H), 4.97(d,1H), 5.04 (s,2H), 5.07 (s,2H), 7.32 (m,10H).

EXAMPLE 29

Ethyl 2-methyl-3-acetylamino-4-(4'-chlorophenylcarbamoyl)-5-oxohexanoate(Example 25) (12 g) was dissolved in trifluoroacetic acid (50 ml),treated with triethylsilane (7.5 ml) and stirred at room temperature for40 hours. The reaction mixture was diluted with diethyl ether andfiltered. The solid was warmed with ethyl acetate then cooled andfiltered to give2-oxo-3,6-dimethyl-4-acetylamino-5-(4'-chlorophenylcarbamoyl)-3,4,5,6-tetrahydro-2H-pyran(ttt isomer) (6.8 g) m.p. 280° C. decomp.

EXAMPLE 30

By the above method was prepared2-oxo-3,6-dimethyl-4-acetylamino-5[(S)-1'-phenylethylcarbamoyl]-3,4,5,6-tetrahydro-2H-pyran,m.p. 327° C. (decomp.) (ttt isomer) using the compound of Example 26 asstarting material.

EXAMPLE 31

To a solution of methyl4-acetylamino-2,2-dimethoxy-6-methyl-3,4-dihydro-2H-pyran-5-carboxylate(13.7 g) (Example 23) in methanol (100 ml) at 20°-25° C. was added water(4.0 ml) and 1N HCl (0.4 ml). The mixture was stirred at 20°-25° C. forfive hours, then the solvents were evaporated at reduced pressure andthe residual gum (13 g) was redissolved in trifluoroacetic acid (100ml), to which was added methylene chloride (25 ml) and triethylsilane(25 ml). The mixture was stirred at 20°-25° C. for 70 hours and then thesolvents were evaporated at reduced pressure. The residue was purifiedby chromatography on K60 silica eluting with ethyl acetate to givemethyl2-oxo-4-acetylamino-6-methyl-3,4,5,6-tetrahydro-2H-pyran-5-carboxylate(4.0 g) m.p. 135°-6° C. (EtOAc/hexane) (4,5-trans: 5,6-trans isomer).

n.m.r.(CDCl₃) 1.41 (d,3H), 1.98 (s,3H), 2.59 (dd,1H), 2.66 (dd,1H), 2.99(dd,1H), 3.77 (s,3H), 4.53 (m,1H), 4.67 (m,1H), 6.70 (d,1H).

EXAMPLE 32

The mixture of isomers from Example 9 was treated as described inExample 24. Ethyl2-methyl-3-benzyloxycarbonylamino-4-methoxycarbonyl-5-oxohexanoate (m.p.51°-3° C.) was purified by chromatography and treated as in Example 27to yield2-oxo-3,6-dimethyl-4-benzyloxycarbonylamino-5-methoxycarbonyl-3,4,5,6-tetrahydro-2H-pyran(ttt isomer) m.p. 144°-6° C., which was purified by chromatography onK60 silica.

Reference Examples

The following Reference Examples illustrate the means by which compoundsof formula I as prepared in Examples 27-32 may be converted intocompounds of formula VI which may in turn be converted into compounds offormula VII.

Reference Example 1

(a) The product of Example 27 (ttt isomer) (3.0 g) was heated in 10 ml6N HCl at 95°-100° C. for 16 hours. The solution was allowed to stand at20° C. for 24 hours, and the crystals were filtered off and dried,giving2-oxo-3,6-dimethyl-4-amino-3,4,5,6-tetrahydro-2H-pyran-5-carboxylic acidhydrochloride 0.9 g., m.p. 220° C. (decomp), the 3,4-trans, 4,5-trans,5,6-trans isomer, n.m.r.(d₆ -DMSO): 1.35 (d,3H), 1.39(d,3H), 2.88(dd,1H), 2.93 (dq, 1H), 3.66 (dd,1H), 4.56 (dq,1H), 8.7 (broad, 3H).

(b) The product of (a) above (0.30 g) was refluxed in absolute ethanol(10 ml) for 3 hours, then cooled to 20° C. Triethylamine (0.20 ml) anddicyclohexylcarbodiimide (0.30 g) were added to the stirred solution,from which a white powder precipitated after 16 hours. The mixture wasfiltered, the filtrates evaporated at reduced pressure and the residueflash chromatographed on K60 silica (EtOAc) to give3-(1-hydroxyethyl)-4-(1-ethoxycarbonylethyl)-trans-azetid-2-one, havingthe relative stereochemistry shown in formula VIIa (0.25 g.).

n.m.r.(CDCl₃): 1.27 (d,3H), 1.30 (t,3H), 1.32 (d,3H), 2.66 (dq,1H), 2.99(dd,1H), 3.78(dd,1H), 4.18 (q,2H), 4.20 (dq,1H), 6.2 (broad,1H).

Reference Example 2

The product of Example 29 (4 g) was dissolved in concentratedhydrochloric acid (20 ml) and heated at 100° C. for 16 hours. Thereaction mixture was evaporated, redissolved in concentratedhydrochloric acid (20 ml) and heated at 100° C. for 24 hours. Themixture was evaporated and the residue was washed with ethyl acetate andtriturated with ethanol to give2-oxo-3,6-dimethyl-4-amino-3,4,5,6-tetrahydro-2H-pyran-5-carboxylic acidhydrochloride (ttt isomer), 0.6 g, m.p. 219° C. with decomposition,which can be further treated by the method of Reference Example 1(b) orby other known methods if desired to yield the corresponding azetidoneintermediate.

Reference Example 3

A solution of the product of Example 31 (1.0 g) in concentratedhydrochloric acid (2.0 ml) was heated at 90°-100° C. for 6 hours. Thesolution was evaporated at reduced pressure and the residual foamtriturated with boiling acetonitrile (10 ml) to give, after filtration,2-oxo-4-amino-6-methyl-3,4,5,6-tetrahydro-2H-pyran-5-carboxylic acidhydrochloride (0.65 g) m.p. 195°-decomp. (trans, trans isomer)

n.m.r.(d₆ -DMSO): 1.35 (d,3H), 2.70 (dd,1H), 2.75 (dd,1H), 3.18 (dd,1H),4.00 (m,1H), 4.52 (m,1H), 8.7 (broad, 3H).

The product can be further treated according to the method of ReferenceExample 1 (b) or by other known methods to yield the correspondingazetidinone intermediate. ##STR5##

We claim:
 1. A tetrahydropyran derivative of formula I:wherein: R1 ishydrogen or alkyl; R2 is alkyl optionally substituted by one or morealkoxy groups or halogen atoms; X is a group of formula --NHCVR⁴ whereinV is oxygen or sulphur, R⁴ is hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, aryl, arylalkyl, amino,mono- or di-alkylamino or a group of the formula --OR⁵ wherein R⁵ isalkyl, substituted alkyl, aryl or arylalkyl, or X is a group of formula--NHSO₂ R^(4a) wherein R^(4a) is alkyl, aryl or a group of formula --CH₂COR^(4b) wherein R^(4b) is alkyl or aryl, and Y is a group of formula--NR⁶ R⁷, wherein R⁶ is hydrogen or alkyl and R⁷ is alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, aryl or arylalkyl or R⁷ is agroup of formula --COOR⁸ wherein R⁸ is alkyl or arylalkyl; or X is ofthe formula --NHSOR^(4a), wherein R^(4a) is defined as hereinabove, andY is alkoxy, cycloalkoxy, arylalkoxy, or of the formula --NR⁶ R⁷,wherein R⁶ and R⁷ are defined as hereinabove;wherein alkyl means(1-6C)alkyl, cycloalkyl means (3-7C)cycloalkyl or bridges(6-9C)bicycloalkyl, aryl means an optionally substituted 5- or6-membered carbocyclic group, arylalkyl means aryl(1-4C)alkyl, alkoxymeans (1-6C)alkoxy, cycloalkoxy means (3-7C)cycloalkoxy or bridged(6-9C)bicycloalkoxy and alkenyl means (2-6C)alkenyl.
 2. The derivativeaccording to claim 1 whereinR¹ is hydrogen or (1-4C)alkyl; R² is alkyloptionally substituted by at least one (1-4C) alkoxy group or halogenatom; X is a group of the formula --NHCVR4 wherein V is oxygen, R4 ishydrogen, alkyl, cycloalkyl (which alkyl and cycloalkyl groups may besubstituted), alkenyl, aryl, arylalkyl, amino, mono- ordi-(1-4C)alkylamino or a group of the formula --OR5 wherein R5 isoptionally substituted alkyl, aryl or arylalkyl, or X is a group of theformula --NHSO₂ R4a, Y is a group of the formula --NR6R7; or X is agroup of the formula --NHSO₂ R4a and Y is cycloalkoxy, arylalkoxy or agroup of the formula --NR6R7, wherein R4a is alkyl, aryl or a group ofthe formula --CH₂ COR4b wherein R4b is alkyl or aryl; and R6 is hydrogenor (1-4C)alkyl and R7 is (1-4C) alkyl, cycloalkyl (which alkyl andcycloalkyl groups may be substituted), aryl or arylalkyl or R7 is agroup of the formula --COOR8 wherein R8 is (1-4C)alkyl or arylalkyl. 3.A compound as claimed in claim 1 wherein R1 represents hydrogen or amethyl group.
 4. A compound as claimed in claim 1 wherein R2 representsa methyl group, optionally substituted by one or more fluorine atoms. 5.A compound as claimed in claim 1 wherein X represents --NHCOR4 whereinR4 represents hydrogen, methyl, ethyl, ethenyl, phenyl, benzyl, methoxy,ethoxy, amino, trifluoroethoxy, trichloroethoxy, phenoxy or benzyloxy.6. A compound as claimed in claim 1 wherein Y represents --NR6R7 whereinR6 is hydrogen and R7 is methyl, ethyl, phenyl, benzyl,alpha-methylbenzyl, methoxycarbonyl or ethoxycarbonyl.